P1455: FIRST-IN-HUMAN TRIAL OF CB-010, A CRISPR-EDITED ALLOGENEIC ANTI-CD19 CAR -T CELL THERAPY WITH A PD-1 KNOCK OUT, IN PATIENTS WITH RELAPSED OR REFRACTORY B CELL NON-HODGKIN LYMPHOMA (ANTLER STUDY)
Authors: L. J. Nastoupil, S. O’Brien, H. E. Holmes, L. Dsouza, D. Hart, E. Matsuda, T. Satterfield-Ledbetter, J. Skoble, E. Garner, M. Bryan, S. Kanner, E. Li, C. T. Thomas, J. Essell
Journal: HemaSphere (2022)

Background: Autologous CAR-T cell therapies have shown significant benefit in the treatment of patients (pts) with relapsed/refractory B cell NHL (r/r B-NHL). Autologous CAR-T cells may have inherent functional deficiencies or yield an inconsistent product and their manufacturing is lengthy and complex. CB-010 is an allogeneic, anti-CD19 CAR-T cell therapy derived from healthy donor T cells. Pts receiving CB-010 do not require leukapheresis or bridging therapy. A next-generation CRISPR technology (Cas9 chRDNAs) that significantly reduces off-target editing was used to generate 3 genome edits in the manufacture of CB-010: knockout (KO) of the TRAC gene to eliminate TCR expression to reduce the risk of GvHD; site-specific insertion of an anti-CD19 CAR into the TRAC locus; and KO of the gene encoding PD-1, designed to limit CAR-T cell exhaustion. Statistically significant preclinical survival benefit across B-NHL subtypes and longer-duration efficacy in vivo compared to similar CAR-T cells without a PD-1 KO support the clinical evaluation of CB-010. Aims: To report the preliminary safety, tolerability, and initial antitumor efficacy of CB-010. Methods: ANTLER is a multicenter, Phase 1 trial in pts with r/r B-NHL. A 3 + 3 dose escalation design followed by expansion at the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) is used. Primary objectives are to determine the RP2D and the safety and tolerability of CB-010. Additional objectives include preliminary antitumor activity, and PK. After serially receiving lymphodepletion therapy with cyclophosphamide (60mg/kg/day x 2 days) and fludarabine (25mg/m2/day x 5 days), pts receive a single dose infusion of CB-010. Results: As of the data-cut-off date of 23 Feb 2022, 6 pts with r/r B-NHL (DLBCL: 2, PMBCL: 1, FL: 2, MCL: 1) were treated with CB-010 at the initial dose level of 40 x106 CAR-T cells. Pts received a median of 3 prior therapies (range 2-8), and all had relapsed on their last therapy. As of the data cut-off, 5 of 6 pts completed the 28-day DLT period. One CRS (Grade 1) has been reported; this pt experienced concurrent CRS and Grade 3 ICANS, characterized as a DLT. The pt received tocilizumab and steroids and recovered from the DLT within 39 hours. There were no cases of GvHD. In addition, 3 of 6 pts developed Grade 3 or 4 AEs within the first 28 days: neutropenia (50%), thrombocytopenia (33%), anemia (16.7%), and hypogammaglobulinaemia (16.7%). Results are preliminary and unaudited. Five out of 6 pts had post baseline tumor assessments and achieved complete response (4) or partial response (1). With a median follow up of 4.5 months (range: 0.6-8.6 months), 4 pts have ongoing responses, 1 pt relapsed at the 6-month evaluation and 1 patient is in the DLT evaluation period. Image:Summary/Conclusion: CB-010, an allogeneic CD19-directed CAR-T cell therapy with a PD-1 KO, demonstrated promising preliminary safety and efficacy in pts with r/r B-NHL at the initial dose level. The study is ongoing, and additional safety and efficacy data will be provided at the meeting. The trial is registered on clinicaltrials.gov (NCT04637763).